U.S. Pat. No. 4,680,299 (Hesson), granted Jul. 14, 1987, describes 4-quinoline-carboxylic acid derivatives as tumor inhibiting agents. Commonly assigned European Patent Application Serial No. 89107099.7, published Nov. 2, 1989 described 4-quinoline-carboxylic acid derivatives as immunomodulatory and anti-inflammatory agents.
U.S. Pat. No. 4,847,381 (Sutherland et. al.,) teaches substituted 4-quinoline-carboxylic acid compounds useful for the treatment of arthritis and useful as immunosuppressive agents.
Presently, cyclosporin A, an immunosuppressive agent, used in combination with other adjunctive therapies, such as azathioprine (AZA and corticosteroids, is the treatment of choice for the prevention of organ transplantation rejection. Other immunosuppressive agents, including but not limited to azathioprine, corticosteroids (such as prednisone), OKT3, FK506, mycophenolic acid or the morpholinethylester thereof, 15-deoxyspergualin, rapamycin, mizoribine, misoprostol and anti-interluekin-2 (IL-2) receptor antibodies have been used or are suggested to be useful in the treatment and/or prevention of organ transplantation rejection.
Use of any of these known immunosuppressive compounds, either along or in combination, is associated with a high incidence of side effects such as nephrotoxicity and/or hepatoxicity. The 4-quinoline-carboxylic acid compounds useful in the present invention have a unique mechanism of action compared to other known immunosuppressive agents, and therefore have not been associated with the nephrotoxicity and hepatoxicity seen with other immunosuppressive agents such as cyclosporin A and AZA. In addition, the combination of a 4-quinoline-carboxylic acid with known immunosuppressive agents has a synergistic effect in terms of inhibition of inflammation in animal models. This synergistic effect is seen at suboptimal doses of each immunosuppressive agent, thus, suggesting that known immunosuppressive agents could be used in combination with a 4-quinoline-carboxylic acid compound, each at lower doses with an associated lower incidence of side effects.